Methods and compositions for extending lifespan

ABSTRACT

The present invention relates to methods for attenuating aging, of health maintenance, and/or treating, or delaying the onset of, an age-related condition or disorder, in a subject comprising administering to the subject an effective amount of (a) one or more compounds that sustain pharmacological activation of xenobiotic metabolism or induce fermentation by gut bacteria to produce substances that activate xenobiotic metabolism enzymes and/or stimulate xenobiotic excretion and (b) one or more chelators. A further aspect of the invention is a composition comprising (a) and (b).

This application claims the benefit of U.S. Provisional Application No.62/410,378, filed Oct. 19, 2016, the entire contents of which are herebyincorporated by reference.

Throughout this application, various publications are referenced,including referenced in parenthesis. Full citations for publicationsreferenced in parenthesis may be found listed at the end of thespecification immediately preceding the claims. The disclosures of allreferenced publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art to which this invention pertains.

FIELD OF THE INVENTION

The present invention relates to methods for attenuating aging, ofhealth maintenance, and/or treating, or delaying the onset of, anage-related condition or disorder, in a subject comprising administeringto the subject an effective amount of (a) one or more compounds thatsustain pharmacological activation of xenobiotic metabolism or inducefermentation by gut bacteria to produce substances that activatexenobiotic metabolism enzymes and/or stimulate xenobiotic excretion and(b) one or more chelators. A further aspect of the invention is acomposition comprising (a) and (b).

BACKGROUND OF THE INVENTION

It is highly desirable to attenuate aging and extend human lifespan, butthe complex etiology of aging leaves potential drug targets unclear.While treatments exist for some symptoms of age related disorders, notreatments are available that address all aspect of agingsimultaneously. There is, therefore a need for new treatment to extendlifespan and treat, or delay the onset of, age-related conditions anddisorders.

Xenobiotic metabolism is a complex, highly regulated and energeticallycostly process whose major function is biotransformation and eliminationfrom the body of lipophilic toxic molecules that are generated asproducts of metabolism (endobiotics) or absorbed from the environment(xenobiotics). This process involves a large battery of enzymes, mainlyexpressed in the liver and the gastrointestinal tract andtranscriptionally regulated by several nuclear receptors (NRs). Phase Ixenobiotic metabolism enzymes, such as cytochrome P450s, catalyzebiotransformation reactions (e.g. hydroxylation) to functionalize thechemically inert xenobiotic molecules for further modifications thatoccur during Phase II. Phase II enzymes (includingUDP-glucuronosyltransferases and glutathione transferases) catalyzecovalent attachment of polar side groups to functionalized xenobioticmolecules, increasing their solubility and promoting their excretion.

Slowing down aging is predicted to yield greater benefits for humanhealth than curing cancer and heart disease combined (Goldman 2013).Despite significant progress in recent years, the underlying biochemicalpathways that determine longevity are not fully understood.

SUMMARY OF THE INVENTION

This invention provides a dietary supplement or food or beverage productcomprising:

-   -   (a) one or more compounds that sustain the pharmacological        activation of xenobiotic metabolism or induce fermentation by        gut bacteria to produce substances that activate xenobiotic        metabolism enzymes and/or stimulate xenobiotic excretion; and    -   (b) one or more chelators.

This invention provides a dietary supplement or food or beverage productcomprising:

-   -   (a) Inulin; and    -   (b) Citric acid.

This invention also provides a dietary supplement or food or beverageproduct comprising:

-   -   (a) Inulin; and    -   (b) Lemon or lime extract, DTPA, EDTA, St. John's wort extract,        Hyperforin, Ginkgo bilogoba extract, Ginkgolide A or B, vitamin        C, Ascorbic acid 6-palmitate, Pantothenic acid (vitamin B-5),        Niacinamide, Allicin (garlic), Lactobionate, Melatonin,        Metformin, L-Dopa, extract Mucuna beans (Mucuna Dopa),        L-Histidine, Quercetin, Curcumin, L-Glutamic acid, succinic        acid, N-Acetil Cysteine, Green tea extract,        Epigallocatechin-3-gallaye, Glutathione, Aspirin, Salicylate,        Glycine, Resveratrol, Genistein, Garnosine, Rapamycin, Lipoic        acid, or Taurine.

This invention also provides a dietary supplement or food or beverageproduct comprising:

-   -   (a) Inulin;    -   (b) St. John's wort extract, Hyperforin, Ginkgo bilogoba        extract, or Ginkgolide A or B, Rapamycin; and    -   (c) Citric acid.

This invention also provides a method of attenuating aging, of healthmaintenance, and/or treating or delaying the onset of, an age-relatedcondition or disorder, the method comprising administering to thesubject an effective amount of:

-   -   (a) one or more compounds that sustain the pharmacological        activation of xenobiotic metabolism or induce fermentation by        gut bacteria to produce substances that activate xenobiotic        metabolism enzymes and/or stimulate xenobiotic excretion; and    -   (b) one or more chelators.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A—Survival curves of B6C3F1/J mice are identical to geneticallyheterogeneous mice used in the NIH interventions testing program (Miller2011)

FIG. 1B—Effects of gender and diet on lifespan of B6C3F1/J mice.Lifespan was not affected by gender or by switching the mice to apurified, chemically defined diet. Consistent with previous reports,dietary restriction significantly extended lifespan.

FIG. 1C—Proscillaridin A extended mouse onset of morbidity by 39.9%(p=5×10−3) and mean lifespan by 16.4% (p=5×10−2). The grey plots in thebackground represent the survival curves of all compounds used in thescreen.

FIG. 1D—Pentetic acid extended mean lifespan by 16.1% (p=5.5×10−2). Thegrey plots in the background represent the survival curves of allcompounds used in the screen.

FIG. 1E—Clofibrate extended maximal lifespan by 20.9% (p=1.4×10−2). Thegrey plots in the background represent the survival curves of allcompounds used in the screen.

FIG. 1F—The compound that most significantly reduced mouse lifespan wasnatural estrogen 17β-estradiol, which reduced mean lifespan by 21%(P=2×10−2). The grey plots in the background represent the survivalcurves of all compounds used in the screen.

FIG. 2—The values depicted next to each bar represent actual percentchange in mean or maximal lifespan relative to controls. The numbers inthe parentheses following the class name represents the number ofcompounds within the respective class. Several drug classes extendedmean and maximal mouse lifespan, with most significant effects achievedby activators of xenobiotic metabolism and chelating agents. The onlydrug class that significantly decreased lifespan contained agonists ofthe estrogen receptor. Maximal lifespan was calculated as the averagelifespan of the 20% longest-lived mice.

FIG. 3. A global view of the screen results highlighting the effects ofindividual activators of xenobiotic metabolism (dark blue) on maximallifespan. Activators of xenobiotic metabolism did not exhibit an alteredweight distribution relative to other compounds, indicating that theirlifespan-extending effects were not due to voluntary caloricrestriction. Overall, mouse weight exhibited a slight but statisticallysignificant negative correlation with lifespan at 5 months(p=7×10−3)—i.e. before the start of compound dosing—as well as at 6months (p=1×10−2) and 12 months (p=4×10−3), consistent with resultsreported by Yuan et al.

FIG. 4 is a histogram comparing the lifespan of the control and compoundtreated B6C3F1/J mice described in Example 1.

FIG. 5 depicts a global view of the screening results, highlighting theeffects of individual activators of xenobiotic metabolism.

FIG. 6A depicts the effect of D-valine on the lifespan of B6C3F1/J mice.

FIG. 6B depicts the effect of inulin on the lifespan of B6C3F1/J mice.

FIG. 7A depicts the effect of Magnesium x3 on the lifespan of B6C3F1/Jmice.

FIG. 7B depicts the effect of Magnesium Hydroxide, Magnesium Acetate andMagnesium Chloride on the lifespan of B6C3F1/J mice.

FIG. 7C depicts the effect of Magnesium x3, Magnesium Hydroxide,Magnesium Acetate, Magnesium Chloride, Calcium Chloride on the lifespanof B6C3F1/J mice (also depicted is the effect of caloric restriction).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by a person of ordinaryskill in the art to which this invention belongs.

As used herein, and unless stated otherwise or required otherwise bycontext, each of the following terms shall have the definition set forthbelow.

As used herein, “about” in the context of a numerical value or rangemeans ±10% of the numerical value or range recited or claimed, unlessthe context requires a more limited range.

The phrase “extending the lifespan” includes statistically significantlyincreasing the life expectancy of a subject (e.g., compared to a controlgroup).

“Therapeutically effective amount” refers to that amount of a compoundof the invention that, when administered to a mammal, is sufficient toeffect treatment, as defined below, of a disease or condition in themammal. The amount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the condition and its severity, the manner of administration, and theage of the mammal to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest, e.g., tissue injury, in a mammal,having the disease or condition of interest, and includes: (i)preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it; (ii) inhibiting the disease orcondition, i.e., arresting its development; (iii) relieving the diseaseor condition, i.e., causing regression of the disease or condition; or(iv) relieving the symptoms resulting from the disease or condition. Asused herein, the terms “disease,” “disorder,” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (so that etiology hasnot yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

It is understood that where a parameter range is provided, all integerswithin that range, and tenths thereof, are also provided by theinvention. For example, “0.2-5 mg/kg/day” is a disclosure of 0.2mg/kg/day, 0.3 mg/kg/day, 0.4 mg/kg/day, 0.5 mg/kg/day, 0.6 mg/kg/dayetc. up to 5.0 mg/kg/day.

Embodiments

This invention provides a dietary supplement or food or beverage productcomprising:

-   -   (a) one or more compounds that sustain the pharmacological        activation of xenobiotic metabolism or induce fermentation by        gut bacteria to produce substances that activate xenobiotic        metabolism enzymes and/or stimulate xenobiotic excretion; and    -   (b) one or more chelators.

In one aspect of the invention (a) is inulin.

In one aspect of the invention (a) is an agonist of nuclear receptorsthat activate xenobiotic metabolism.

In one aspect of the invention the agonist of nuclear receptors thatactivate xenobiotic metabolism is selected from the group consisting ofconstitutive androstane receptor (CAR) agonists, pregnane X receptor(PXR) agonists, or a peroxisome proliferator-activated receptor α(PPARα) agonist.

In one aspect of the invention the agonist of nuclear receptors thatactivate xenobiotic metabolism is clofibrate.

In one aspect of the invention (b) is diethylenetriaminepentaacetic acid(DTPA).

This invention also provides a dietary supplement or food or beverageproduct comprising:

-   -   (a) Inulin; and    -   (b) Citric acid.

In one aspect of the invention the dietary supplement or food orbeverage further comprises magnesium or a magnesium salt.

In one aspect of the invention the dietary supplement or food orbeverage product comprises, per serving:

-   -   (a) 5-10 grams of inulin; and    -   (b) 1-2 grams of citric acid.

In one aspect of the invention the dietary supplement or food orbeverage product comprises 200-300 milligrams of magnesium or amagnesium salt per serving.

In one aspect of the invention the dietary supplement or food orbeverage product comprises 250 milligrams of magnesium or a magnesiumsalt per serving.

This invention also provides a dietary supplement or food or beverageproduct comprising:

-   -   (a) Inulin; and    -   (b) Lemon or lime extract, DTPA, EDTA, St. John's wort extract,        Hyperforin, Ginkgo bilogoba extract, Ginkgolide A or B, vitamin        C, Ascorbic acid 6-palmitate, Pantothenic acid (vitamin B-5),        Niacinamide, Allicin (garlic), Lactobionate, Melatonin,        Metformin, L-Dopa, extract Mucuna beans (Mucuna Dopa),        L-Histidine, Quercetin, Curcumin, L-Glutamic acid, succinic        acid, N-Acetil Cysteine, Green tea extract,        Epigallocatechin-3-gallaye, Glutathione, Aspirin, Salicylate,        Glycine, Resveratrol, Genistein, Garnosine, Rapamycin, Lipoic        acid, or Taurine.

In one aspect this dietary supplement or food or beverage product ofcomprises magnesium or a magnesium salt.

In one aspect the dietary supplement or food or beverage productcomprises:

-   -   (a) Inulin;    -   (b) St. John's wort extract, Hyperforin, Ginkgo bilogoba        extract, or Ginkgolide A or B, Rapamycin; and    -   (c) Citric acid.

In one aspect this dietary supplement or food or beverage product offurther comprises magnesium or a magnesium salt.

In one aspect, the dietary supplement or food or beverage product is:

-   -   (a) yogurt;    -   (b) porridge;    -   (c) bread;    -   (d) baby food;    -   (e) a sports drink;    -   (f) an energy bar;    -   (g) chocolate.

In one aspect the dietary supplement is in the form of a tablet orcapsule for oral ingestion.

It is thought that the dietary supplements of the invention increaselifespan or attenuate aging by activating the distinct pathwaysdescribed herein.

This invention also provides a method of attenuating aging, of healthmaintenance, and/or treating or delaying the onset of, an age-relatedcondition or disorder, the method comprising administering to thesubject an effective amount of:

-   -   (a) one or more compounds that sustain the pharmacological        activation of xenobiotic metabolism or induce fermentation by        gut bacteria to produce substances that activate xenobiotic        metabolism enzymes and/or stimulate xenobiotic excretion; and    -   (b) one or more chelators.

In one aspect the administration prolongs the lifespan of the subjectrelative to the lifespan of the subject in the absence of theadministration.

In one aspect the administration treats or delays the onset of theage-related disease in the subject relative to the subject in theabsence of the administration.

In one aspect of the method (a) is inulin.

In one aspect of the method (a) is an agonist of nuclear receptors thatactivate xenobiotic metabolism.

In one aspect of the method the agonist of nuclear receptors thatactivate xenobiotic metabolism is selected from the group consisting ofconstitutive androstane receptor (CAR) agonists, pregnane X receptor(PXR) agonists, or a peroxisome proliferator-activated receptor α(PPARα) agonist.

In one aspect of the method the agonist of nuclear receptors thatactivate xenobiotic metabolism is clofibrate.

In one aspect of the method (b) is: Lemon or lime extract, DTPA, EDTA,St. John's wort extract, Hyperforin, Ginkgo bilogoba extract, GinkgolideA or B, vitamin C, Ascorbic acid 6-palmitate, Pantothenic acid (vitaminB-5), Niacinamide, Allicin (garlic), Lactobionate, Melatonin, Metformin,L-Dopa, extract Mucuna beans (Mucuna Dopa), L-Histidine, Quercetin,Curcumin, L-Glutamic acid, succinic acid, N-Acetil Cysteine, Green teaextract, Epigallocatechin-3-gallaye, Glutathione, Aspirin, Salicylate,Glycine, Resveratrol, Genistein, Garnosine, Rapamycin, Lipoic acid, orTaurine.

In one aspect of the method (b) is diethylenetriaminepentaacetic acid(DTPA).

In one aspect of the method the administration prolongs the lifespan ofthe subject more than the individual effect of the administration ofeither (a) or (b).

In one aspect of the method the administration prolongs the lifespan ofthe subject synergistically, i.e. more than the sum of the individualeffect of the administration of (a) and (b).

In one aspect the method comprises administering to the subject aneffective amount of one or more compound selected from the groupconsisting of:

-   -   (a) a COX inhibitor;    -   (b) an antiparasitic agent;    -   (c) an acetylcholinesterase inhibitor;    -   (d) an adenosine receptor antagonist;    -   (e) a selective estrogen receptor modulator.

In one aspect the method comprises administering to the subject aneffective amount of a magnesium salt.

In one aspect the method comprises the magnesium salt is Magnesiumhydroxide, Magnesium acetate, or magnesium chloride.

In one aspect the method comprises administering to the subject aneffective amount of citric acid.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.

Active Compounds

Preferable xenobiotic metabolism activator compounds include

-   -   ginkgo biloba, specifically Ginkgolide A and B,    -   and St. John's Wort.

Preferable chelator compounds include:

-   -   Allicin (DS, extract of garlic)    -   Aminoguanidine,    -   Ascorbic acid 6-palmitate,    -   Aspirin,    -   Carnosine,    -   Curcumin,    -   Cysteine,    -   EDTA (DS)    -   Epigallocatechin-3-gallate,    -   extract Mucuna beans (Mucuna Dopa),    -   Genistein,    -   Glutathione    -   Glycine,    -   Green tea extract,    -   Guanidine,    -   Lactobionate,    -   L-Dopa (including Mucuna Dopa)    -   L-Glutamic acid,    -   L-Histidine (DS)    -   Melatonin,    -   Metformin    -   Methyl Salicylate,    -   Niacinamide,    -   Pantothenic acid (vitamin B-5),    -   Quercetin,    -   Resveratrol,    -   Salicylate,    -   Vitamin C.

Particularly preferable chelators are those which are shown to provide10% or greater effect and include: Ascorbic Acid 6-Palmitate (AscorbylPalmitate), Citric Acid, D-Pantothenic Acid (Vitamin B-5), Melatonin,and Niacinamide (Vitamin B-3), and diethylenetriaminepentaacetic acid(DTPA).

Preferable magnesium compounds are those which are shown to provide 10%or greater effect and include: Magnesium Acetate, Magnesium Hydroxideand Manganese Sulfate.

Other preferable compounds which are those which are shown to provide10% or greater effect and include: Hemicalcium and Peppermint Oil.

Xenobiotic metabolism activator compounds useful in the methodsdescribed herein, include, for example, compounds that act as agonistsof nuclear receptors that activate or induce xenobiotic metabolism.

Suitable classes of agonist compounds include, but are not limited to,constitutive androstane receptor (CAR) agonists, pregnane X receptor(PXR) agonists and peroxisome proliferator-activated receptor α (PPARα)agonists, and any combination thereof.

Suitable examples of CAR agonists include, but are not limited to6,7-dimethylesculetin, acetaminophen, artemisinin, atorvastatin,cerivastatin, CITCO ((6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-0-(3,4-dichlorobenzyl)oxime), fluvastatin,orphenadrine, phenobarbital, phenytoin, pravastatin, simvastatin, andcombinations thereof.

Suitable examples of PXR agonists include, but are not limited to,4-hydroxytamoxifen, androstenol, artemisinin, avasimibe, BK8644,bosentan, bromopropylate, butamifos, carbamazepine, cis-guggulsterone,clotrimazole, desmethoxyyangonin, dexamethasone, dihydromethysticin,dymuron, efavirenz, esprocarb, ethion, etoposide, flucythrinate,forskolin, hyperforin (hypericum perforatum extract or St John's wort),indanofan, isofenphos, isradipine, kava extract, lithocholic acid,lovastatin, meclizine, methadone, metlachlor, mevastatin, mifepristone,nicardipine, nifedipine, paclitaxel, PCN(pregnenolone-16a-carbonitrile), phenobarbital, piperophos,pretilachlor, pyributicarb, rifampicin, ritonavir, spironolactone, SR12813, tamoxifen, thenylchlor, topiramate, topotecan,trans-guggulsteone, triadimefon, ursodeoxycholic acid, and combinationsthereof.

Suitable examples of PPARα agonists include, but are not limited to,aleglitazar, arachidonic acid, bezafibrate, ciprofibrate, clinofibrate,clofibrate, clofibric acid, clofibride, CP 77 5146, eicosapentaenoicacid, etofibrate, fenofibrate, fenofibric acid, gemfibrozil, GW 7 64 7,linoleic acid, muraglitazar, nafenopin, oleic acid, oleylethanolamide,palmitic acid, palmitoleic acid, palmitoylethanolamide, pioglitazone,pirinixic acid, rivoglitazone, ronifibrate, rosiglitazone, saroglitazar,simfibrate, stearic acid, tesaglitazar, troglitazone, WY-14643, andcombinations thereof.

Suitable examples of cardiac glycosides include, but are not limited to,acetyldigitoxin, acetyldigoxin, arenobufagin, bufotalin, cinobufagin,cymarm, deslanoside, Digitalis leaves, digitoxin, digoxin, gitoformate,K-strophanthin, lanatoside C, marinobufagin, metildigoxin, ouabain,peruvoside, proscillaridin (e.g., proscillaridin A), scilliroside, andcombinations thereof.

Suitable examples of COX inhibitors include, but are not limited to,aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) (such asibuprofen, piroxicam, mefenamic acid, diclofenac, flurbiprofen, andindomethacin), COX-2 inhibitors (such as celecoxib), and combinationsthereof.

Suitable examples of antiparasitic agents include, but are not limitedto, mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine,ivermectin, niclosamide, praziquantel, albendazole, praziquantel,rifampin, amphotericin B, melarsoprol, eflornithine, metronidazole,tinidazole, miltefosine, and combinations thereof.

Suitable examples of acetylcholinesterase inhibitors include, but arenot limited to, donepezil, galantamine, caffeine,delta9-tetrahydrocannabinol (THC), physostigmine, neostigmine,pyridostigmine, ambenonium, demecarium, rivastigmine, tacrine,edrophonium, huperzine A, ladostigil, ungeremine, lactucopicrin, andcombinations thereof.

Suitable examples of adenosine receptor antagonists include, but are notlimited to, caffeine, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX),cyclopentyltheophylline (CPT), istradefylline, SCH-58261, dyphylline,theophylline, theobromine, proxyphylline, pentoxiphylline, etofylline,aminophylline, dimenhydrinate, and combinations thereof.

Suitable examples of chelators include, but are not limited to,2,3-dimercapto-1propanesulfonic acid (DMPS), alpha lipoic acid, BAPTA,citric acid, deferasirox, deferiprone, deferoxamine (DFO), dimercaprol(BAL), dimercaptosuccinic acid (DMSA), ethylene glycol tetraacetic acid(EGTA), ethylenediaminetetraacetic acid (EDTA), penicillamine, penteticacid (DTPA), Prussian blue, succinic acid, tartaric acid,triethylenetetramine (TETA), N-acetyl-L-cysteine, aspartic acid,histidine, glutamic acid, glutathione, etindronic acid, methionine,selenomethionine, taurine, alendronic acid, clodronic acid, tiopronin,diethyldithiocarbamate, and combinations thereof.

Additional inducers of xenobiotic metabolism include, but are notlimited to, 2-naphthoflavone, 3-methylcholanthrene, dioxin, metyrapone,decitabine, trichostatin A, hydroxymethylpyrene, indolo [3,2-b]carbazole, phenethylisothiocyanate, isothiocyanatomethylbenzene,sulforaphane, coumestrol, testosterone, dihydrotestosterone,indole-3-carbinol, 3-nitrobenzanthrone,2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole, primaquine, iprodione,ketoconazole, deltamethrin, omeprazole, pentachlorophenol, fipronil,sulindac, 3-aminobenzanthrone, 6-nitrochrysene, ltraconazole,Enilconazole (imazalil),2-[2-(acetylamina)-4-(diallylamina)-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole(PTBA-8),9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl)-6H-pyrido(4,3-b)-carbazole-1-carboxamide,carbaryl, 6-formylindolo[3,2-b]carbazole,2-[2-(acetylamino)-4-(diethylamino)-5-methoxypheny1]-5-amino-7-bromo-4-chloro-2H-benzotriazole(PB TA-7), chlorpyrifos, sulindac sulfone, fluconazole, permethrin,ascorbigen, DEET (N,N-diethyl-metatoluamide), clevidipine, emodin,4-biphenylamine, nevirapine, efavirenz, chlorpyrifos oxon, ibrolipim,isoniazid, ethanol, tretinoin, fandosentan potassium, modafinil,trazodone, trimeprazine, etoposide, doxorubicin, rifabutin,alpha-naphthoflavone, progesterone, ethambutol, benzil,1-methylphenanthrene, olopatadine, ethionamide, quercetin,4-hydroxynonenal, oltipraz, butanoate, resveratrol, paraquat, alphalipoic acid, carnoslc acid, camosol, oxaliplatin, paclitaxel,nicotinamide, azathioprine, eugenol, chlorophyllin,2-tert-butylhydroquinone, hydrocortisone, procainamide, corticosterone,medroxyprogesterone 17-acetate, dopamine, 4-nitrophenol, bilirubin,glycyrrhizic acid, nanngenm, saccharolactone, isopropyl thiogalactoside,naphthyl glucuronide, epigallocatechin gallate, imipramine, serotonin,nicotine, cotinine, propylpyrazoletriol, genistein, pyrazole, ITE2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), MeBIO((2′Z,3′E)-6-bromo-1-methylindirubin-3′-oxime), pifithrin-a, andcombinations thereof.

Routes of Administration

Any route of administration may be selected for use in the methodsdescribed herein. For instance, the route of administration may beselected from oral, nasal, buccal, rectal, vaginal, ophthalmic,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intratumoral, spinal, intrathecal, intra-articular,intra-arterial, sub-arachnoid, sublingual, oral mucosal, pulmonary,bronchial, lymphatic, intra-uterine, subcutaneous, intratumor,integrated on an implantable device, intradural, intracortical, dermal,epidermal, transdermal, vaginal, rectal, ocular (for examples throughthe conjunctiva), intraocular, uretal, and parenteral. A preferred routeof administration is oral.

Dosages

The actual dosage amount of the active compound(s) administered to asubject may be determined by physical and physiological factors such asage, sex, body weight, severity of condition, the type of disease beingtreated, previous or concurrent therapeutic interventions, idiopathy ofthe subject and on the route of administration. These factors may bedetermined by a skilled artisan. The practitioner responsible foradministration will typically determine the concentration of activecompound(s) in a composition and appropriate dose(s) for the individualsubject.

In one embodiment, a human subject is administered the daily dose offrom about 0.01 mg/kg to about 1000 mg/kg of the active compound(s).Preferably, the dosage level will be about 0.1 to about 250 mg/kg perday, more preferably about 0.5 to about 100 mg/kg per day. A suitabledosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range thedosage may be about 0.05 to 0.5, about 0.5 to 5 or about 5 to 50 mg/kgper day. For oral administration, the compositions are preferablyprovided in the form of tablets containing 0.1 to 1000 mg of the activecompound(s), for example, about 0.1, 0.5, 1, 5, 10, 15, 20, 25,50, 75,100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 550,600, 650, 700, 750, 800, 850, 900, 950 or about 1000 mg of the activecompound(s).

The compounds may be administered on a routine schedule. As used hereina routine schedule refers to a predetermined designated period of time.The routine schedule may encompass periods of time which are identicalor which differ in length, as long as the schedule is predetermined. Forinstance, the routine schedule may involve administration twice a day,every day (once daily), every two days, every three days, every fourdays, every five days, every six days, a weekly basis, a monthly basisor any set number of days or weeks there-between.

In certain embodiments, the compounds described herein can beadministered over an extended period of time, for example, for at least1, at least 2, at least 6, at least 12, at least 18 or at least 24months (or, for example, for 18 months, 2 years, 21 h years, or for 3years).

In one embodiment, the methods described herein do not involvecoadministration of estrogen receptor agonists (including endogenousestrogens, such as 17˜-estradiol and estrone, and synthetic estrogens,such as diethylstilbestrol and hexestrol).

Pharmaceutical Compositions

The compounds described herein may be administered (e.g., orally) in theform of a solid or liquid dosage form. In both, the compounds may becoated in a material to protect them from the action of acids and othernatural conditions which may inactivate the compounds. The compounds maybe formulated as aqueous solutions, liquid dispersions, (ingestible)tablets, buccal tablets, troches, capsules, elixirs, powders, granules,ointments, adhesive skin patches, sprays, suspensions, syrups, andwafers. The dosage forms may include pharmaceutically acceptableexcipients, diluents, and/or carriers known in the art, such as binders,disintegrating agents, emulsifiers, lubricants, flavorants,antioxidants, and preservatives. Liquid dosage forms may includediluents such as saline or an aqueous buffer.

The active compounds can be administered as foods, food additives,edible soluble films, drinks, medicinal agents, and feeds for domesticand wild animals. The drinks may be non-alcohol drinks or alcoholdrinks. Examples of non-alcohol drinks include carbonated drinks,non-carbonated drinks (such as fruit juice, and nectar), soft drinks,sports drinks, tea, coffee, and hot chocolate. The alcohol drinks may bein the form of, for example, beer, low-malt beer, third-category beer,sake, umeshu, wine, champagne, liqueur, chuhai, or medicated liquor.

For use as a food material or food additive (e.g., human food or animalfood, such as dog or cat food or feed for poultry, cows, or pigs), theactive compound may be in the form of, for example, a tablet, a capsuleformulation, a solid agent (such as a powder and a granule) dissolved indrinks, a semi-solid such as jelly, a liquid (such as drinking water),and a high-concentration solution diluted before use. Optionalcomponents, such as vitamins, carbohydrates, dyes, and flavoring agentscommonly added to food may be appropriately mixed. The food may be givenin any form, including a liquid and a solid.

Dietary Supplements

The dietary supplement may also comprise one or more compounds known tothose of ordinary skill to be useful in dietary supplements, including,but not limited to, vitamins, minerals (e.g., magnesium), fatty acids,antioxidants, amino acids, palatants and nutraceutical additives, andany combination thereof. See the National Institute of Health DietarySupplement Database: http://www.dsld.nlm.nih.gov/dsld. For example, thedietary supplement may also include one or more calcium-containingmaterials such as calcium carbonate, stannol esters, hydroxycitric acid,vitamins, minerals, herbals, spices and mixtures thereof. Examples ofvitamins that are available as additional ingredients include, but arenot limited to, vitamin A (retinal), vitamin D (cholecalciferol),vitamin E group (alpha-tocopherol and other tocopherols), vitamin Kgroup (phylloquinones and menaquinones), thiamine (vitamin B1),riboflavin (vitamin B2), niacin, vitamin B6 group, folic acid, vitaminB12 (cobalamins), biotin, vitamin C (ascorbic acid), and mixturesthereof. The amount of vitamin or vitamins present in the final productis dependent on the particular vitamin. Examples of minerals that areavailable as additional ingredients include, but are not limited to,calcium, magnesium, phosphorus, iron, zinc, iodine, selenium, potassium,copper, manganese, molybdenum and mixtures thereof. As is the case withvitamins, the amount of mineral or minerals present in the dietarysupplement is dependent on the particular mineral.

Subject

The subject is a mammal, such as a human, or, for example, a domestic orwild animal, such as a chicken, quail, ostrich, horse, bird, dog, cat,cow or pig. Preferably, the subject is a human, such as a male or femaleadult. For example, the subject may be an adult who is between 18 and 30years old, between 30 and 40 years old, between 40 and 50 years old,between 50 and 60 years old, between 60 and 70 years old, and between 70and 80 years old.

REFERENCE TO OTHER PUBLICATIONS OR REFERENCES AND TO THE EXPERIMENTALDETAILS

All publications and other references mentioned herein are incorporatedby reference in their entirety, as if each individual publication orreference were specifically and individually indicated to beincorporated by reference. Publications and references cited herein arenot admitted to be prior art.

This invention will be better understood by reference to theExperimental Details which follow, but those skilled in the art willreadily appreciate that the specific experiments detailed are onlyillustrative of the invention as defined in the claims which followthereafter.

Experimental Details

Examples are provided below to facilitate a more complete understandingof the invention. The following examples illustrate the exemplary modesof making and practicing the invention. However, the scope of theinvention is not limited to specific embodiments disclosed in theseExamples, which are for purposes of illustration only.

EXAMPLE 1

In order to improve our understanding of the underlying biochemicalpathways that determine longevity, the inventors conducted a large-scalescreen in mice, testing the effects of 1033 well-defined pharmacologicalcompounds on lifespan. The majority of compounds included drugscurrently used in medicine and drug-like molecules, with wide range oftargets that span the entire pharmacological space.

The compounds were clustered into 62 drug classes based on theirmechanism of action or cellular target. Screening a wide range of knowncompounds could potentially resolve two challenges. First, to analyzehow distinct drug classes with common mechanisms of action affect agingin mammals. Second, to determine with no bias or predispositions whichof the current pharmacological drugs can extend lifespan.

In this study, the inventors used a strain of long-lived B6C3F1 hybridmice (C57BL/6J♀×C3H/HeJ♂) with well-characterized aging dynamics (Lipman1999, Turturro, 1999). The study design was shaped to test a largenumber of compounds, yet still identify individual compounds thatsignificantly extend lifespan by at least 15%. Each treatment groupincluded 15 female mice per compound, while 335 females were used ascontrols. Three additional control groups included 60 female mice ondietary restriction (60% ad libitum), 60 female mice on a purified diet,and 60 male mice as gender control. Each compound treatment and dietintervention were administered to mice starting at 5 months of age, andcontinued throughout their lifespan. The primary endpoint was mousemortality, from which we calculated mean lifespan, maximal lifespan, andthe onset of morbidity for each experimental group. To calculate thestatistical significance, the mean lifespan, maximal lifespan, and theonset of morbidity for each individual compound and drug class werecompared to the lifespan distribution of untreated mice. This comparisonyielded raw p-values, which were then adjusted to control for the falsediscovery rate (i.e. for the fact that >1000 compounds were tested inthe screen) (Benjamini, 1995).

Inventors identified 2 out of 62 drug classes in total that exhibited byfar the most significant extension of lifespan—xenobiotic metabolismactivators and chelating agents (FIG. 2). In addition, the inventorsidentified four individual compounds that significantly extended meanand/or maximal lifespan—Clofibrate, Pentetic Acid, Inulin, andProscillaridin A. Finally, only one compound significantly shortenedlifespan—1β-estradiol (mean lifespan by 21%; FIG. 1F).

Xenobiotic metabolism activators exhibited the most significantextension of both mean, and maximal lifespan (p=2.0×10−6 and p=6.2×10−8respectively). These comprised molecules that are strong agonists ofnuclear receptors constitutive androstane receptor (CAR), pregnane Xreceptor (PXR), and peroxisome proliferator-activated receptor alpha(PPARα), which together are known to induce xenobiotic metabolismenzymes.

Xenobiotic metabolism has been previously implicated in longevity indiverse organisms by studies demonstrating that activation of xenobioticmetabolism and increased xenobiotic resistance are common tobest-studied and most robust means of lifespan extension (Amador-Noguez2007, Gems 2005, McElwee 2004, Steinbaugh 2012, Zimniak 2008). Forexample, it was demonstrated by gene expression and metabolomic studiesin rodents that dietary restriction upregulates the expression of manydetoxification enzymes (Steinbaugh 2012, Wen 2013). It was alsodemonstrated in various long-lived animal models, includingCaernohabditis elegans daf-2 mutants and dwarf mouse strains, thatlifespan extension is associated with upregulated expression ofdetoxification enzymes (Amador-Noguez 2007, McElwee 2005, Steinbaugh2012, McElwee 2007). Finally, the best-studied example ofpharmacological extension of mouse lifespan using rapamycin is alsocharacterized by upregulated expression of xenobiotic metabolism genes(Steinbaugh 2012). Here, inventors present evidence that directpharmacological activation of xenobiotic metabolism can be sufficient toextend mammalian lifespan.

Xenobiotic metabolism is a highly regulated process whose major functionis biotransformation and elimination from the body of lipophilic toxicmolecules that are normally generated as products of metabolism (a.k.a.endobiotics), or absorbed from the environment (a.k.a. xenobiotics)(Omiecinski 2011). The function of xenobiotic metabolism is carried outby a battery of detoxification enzymes that are categorized into severaldistinct phases, including phase I and phase II enzymes. Phase Ienzymes, such as cytochrome P450s, catalyze biotransformation reactions(e.g. hydroxylation) to functionalize the chemically inert xenobioticmolecules, while phase II enzymes (includingUDP-glucuronosyltransferases and glutathione S-transferases) catalyzecovalent attachment of polar side groups to functionalized xenobiotics,increasing their solubility and promoting their excretion. Other factorsinvolved in xenobiotic metabolism are drug transporters that promotexenobiotic excretion.

The largest extension of maximal lifespan by an individual compound wasexhibited by clofibrate (21%; FIG. 1F). Interestingly, clofibrate isalready known as a strong agonist of PPARα and has classically been usedto activate xenobiotic metabolism (Guo 2007). Recently it has also beendemonstrated that clofibrate extends lifespan in C. elegans, and thiseffect is dependent on a C. elegans homolog of mammalian PPARα(Brandstadt 2013). Therefore, in accord with previous findings, thelifespan extending effect of clofibrate may be the direct result ofactivation of cellular detoxification through PPARα activation.

Chelating agents are the second drug class to induce significantextension of mean and maximal lifespans (p=1.6×10−5 and p=3.4×10−4respectively). Furthermore, pentetic acid (diethylene triamenepentaacetic acid), a strong chelator was one of the top individual lifeextending compounds, extending mean lifespan by 16% (FIG. 1D; p=5×10−2).Interestingly, it was also demonstrated recently that treatment withchelating agents could extend lifespan in C. elegans (Klang 2014).Pentetic acid is an EDTA-like strong chelator that is currently underdevelopment as an oral drug to remove radioactive ions.

The canonical function of chelators in organisms is to facilitate theremoval of metal ions such as lead, arsenic, cadmium, mercury, iron,copper, etc. Transition metals, such as iron and copper, are known tocatalyze the nonspecific formation of advanced glycation end-products(AGEs). Nonenzymatic and nonspecific glycoation of proteins, nucleicacids, and lipids (ALEs) has been linked to crosslinking of molecules,cell senescence and stiffening of tissues at old age. In addition totissue damage, AGEs are also sensed by RAGE receptor that induceschronic inflammation. Interestingly it was demonstrated that allcurrently known agents that prevent formation of AGEs act as chelators,suggesting that chelation of transition metal ions can extend lifespanthrough prevention of AGE formation.

Chelation agents can also protect from heavy metal poisoning. Theaccumulation of these metals at low levels in organisms can exert severetoxicities and pathologies, in addition to the heavy acute toxicitiesthey can cause in the event of poisoning (Sears 2013, Apostoli 2006).Heavy metals exert their direct toxic effects by binding to tissues,causing DNA damage, binding to proteins and interfering with functionsof zinc and magnesium, immunosensitization, and immunosuppression (Sears2013, Apostoli 2006). Heavy metals can also generate reactive oxygenspecies and oxidative stress, mainly by catalyzing the formation ofhydroxyl radicals. Our results suggest that chelation therapy can slowdown aging through one or more mechanisms.

Inventors also identified five drug classes that extended only maximallifespan with marginal statistical significance, consisting ofacetylcholinesterase inhibitors, adenosine receptor antagonists,antiparasitic agents, cyclooxygenase (COX) inhibitors, and selectiveestrogen receptor modulators (p˜1×10−3).

In addition to clofibrate and pentetic acid, another two compoundssignificantly extended lifespan. First, Proscillaridin A, a cardiacglycoside, extended mean lifespan by 16% and onset of morbidity by 40%(FIG. 1C). Second, inulin, a dietary fiber, extended mean lifespan by16% and maximal lifespan by 18%. Proscillaridin A has not beenpreviously implicated in longevity and thus represents novel anti-agingpharmacological agent. On the other hand, Inulin is exceptionallyinteresting because it may also act by activating xenobiotic metabolism.Inulin is a soluble fiber that cannot be broken down by mammalian cells;however, it can be metabolized by certain kinds of beneficial gutbacteria, helping to promote a healthy gut flora (Macfarlane 2008).Inulin fermentation by gut bacteria produces substances that inducexenobiotic metabolism enzymes and stimulate xenobiotic excretion(Buddington 2002, Sauer 2007), suggesting that inulin may extendlifespan by activating xenobiotic metabolism. The role of gut flora inaging is also supported by a recent study demonstrating therestructuring of the gut microbiome during aging in mice, and itsmodulation by caloric restriction (Zhang 2013).

In addition to the compounds listed above, the screen identified over 50compounds that extended mean mouse lifespan by >10%. This number is overthree-fold higher than that expected by chance, indicating that thesecompounds present a strong pool of candidates for future longevitystudies. Thus, the screen identified a number of drugs whoseeffectiveness in extending longevity could potentially match that ofrapamycin (Harrison 2009, Miller 2011).

Surprisingly, clustering all compounds in the screen and comparing themto controls revealed that on average compound treatment correlated withincreased lifespan (+1.5%, p<10−10; FIG. S2). This phenomenon isreminiscent of hormesis, i.e. when low-dose treatment with toxiccompounds can exhibit beneficial effect (Gems 2008). In fact, it wasalso proposed the hormetic effect is mediated by activation ofxenobiotic metabolism (Gems 2008). Naturally the majority of our testedcompounds are themselves substrates of xenobiotic metabolism. It ispossible that the slight lifespan extension by majority of compounds isalso mediated through activation of xenobiotic metabolism. In additionmany drugs are known to act as chelating agents (Nagai 2012). Even suchdrugs as aspirin and metformin can act as chelating agents. Thereforethe slight extention of lifespan by majority of compounds can in somecases be explained by their chelating activity.

The only drug class that significantly shortened mouse lifespancomprised estrogen receptor (ER) agonists (maximal p=1.5×10−5; meanp=9.0×10−3; FIG. 2), including endogenous estrogens 17β-estradiol andestrone, as well as synthetic estrogens, e.g. diethylstilbestrol andhexestrol. Furthermore, the only individual compound to significantlyshorten lifespan was 17β-estradiol, shortening mean lifespan by 21%(FIG. 1F; p=2×10−2). It is worth noting that drugs classified asselective estrogen receptor modulators (SERMs) that antagonize ERsignaling as a group extended maximal lifespan (p=1×10−3; FIG. 2),consistent with the hypothesis that hyper-activation of ER signalingshortens lifespan.

These results are consistent with known roles of estrogen signaling inreproduction and growth—processes known to antagonize longevity (Bartke2013). In particular, estrogen signaling promotes secretion of growthhormone (GH) and functionally interacts with the IGF-1 pathway (Hewitt2010, Kahlert 2000, Hamelers 2003), thus directly stimulating specificpro-growth pathways whose inactivation prolongs lifespan in severalexperimental model systems (Bartke 2013). Lastly, the discovery thatmammalian lifespan can be extended by activators of xenobioticmetabolism and chelators and shortened by estrogen and estrogen-likecompounds is consistent with current evolutionary theories of aging,where it is postulated that the lifespan of a species is determined byits choice of allotment of resources to competing, energetically costlyevolutionary strategies: detoxification and maintenance vs. reproductionand growth (Gems 2005, Zimniak 2008, Bartke 2013, Gems 2013, Kirkwood1977, Kirkwood 2000).

In conclusion, by conducting an unbiased, large-scale screen theinventors were able to elucidate a comprehensive map of pharmacologicaleffects on mammalian longevity. Most importantly, the results indicatethat mammalian lifespan can be extended through pharmacologicalactivation of xenobiotic metabolism or treatment with chelating agents.This suggests that xenobiotic- and endobiotic-mediated damage, anddamage caused by heavy metal ions, are major contributors to aging andare determinants of lifespan. It is also noteworthy that xenobioticmetabolism and removal of heavy metals through chelation are bothdetoxification systems. We hypothesize that nuclear receptorsresponsible for regulation of xenobiotic metabolism epitomize an idealpharmacological target for anti-aging drugs that could be exploited inthe near future for the development of lifespan extending compounds forhumans. In addition, combining xenobiotic metabolism activators withchelation therapy should produce synergistic effects.

The inventors also identified inulin—a dietary supplement, whichexhibited lifespan extension likely through indirect activation ofxenobiotic metabolism. Inulin is already widely used as a prebiotic andis known for its beneficial effects to human health (Macfarlane 2008,Tuohy 2007). This means that inulin could be tested for effects on humanaging immediately. If the effect of inulin on mouse lifespan isrecapitulated in humans, the consequences for human health are expectedto be unprecedented, surpassing the eradication of multiple age-relateddisorders (Goldman 2013).

Conclusion

The inventors found that 2 drug classes exhibited significant mean andmaximal lifespan extension, consisting xenobiotic metabolism activatorsand chelating agents. The results suggest that xenobiotic- andendobiotic-mediated damage, and damage caused by metal ions, constitutethe major determinants of mammalian longevity. In the case of chelatingagents, the most likely explanation of their lifespan extending effectis prevention of formation of Advanced Glycation End products (AGEs) dueto chelation of transition metal ions such as Fe2+ and Cu2+. Inaddition, the inventors identified individual compounds, including anactivator of xenobiotic metabolism, a chelating agent, and a commondietary supplement that significantly extended lifespan. This studydemonstrates novel anti-aging strategies potentially applicable tohumans.

EXAMPLE 2

A third group of compounds that inventors have found exhibit significantlifespan extension are Magnesium compounds. Inventors performed theexperiments as in Example 1 using Magnesium Acetate, Magnesium Chloride,Magnesium Hydroxide along with caloric restriction and Calcium Chloride.See FIGS. 7A, 7B and 7C. Inventors found that the Magnesium compoundssignificantly extended the life span of the mice. This class ofcompounds is thought to act on a different pathway from the pathwaysdescribed in Example 1.

REFERENCES

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What is claimed is:
 1. A dietary supplement or food or beverage productcomprising: (a) one or more compounds that sustain the pharmacologicalactivation of xenobiotic metabolism or induce fermentation by gutbacteria to produce substances that activate xenobiotic metabolismenzymes and/or stimulate xenobiotic excretion; and (b) one or morechelators.
 2. The dietary supplement or food or beverage product ofclaim 1 wherein (a) is inulin.
 3. The dietary supplement or food orbeverage product of claim 1 wherein (a) is an agonist of nuclearreceptors that activate xenobiotic metabolism.
 4. The dietary supplementor food or beverage product of claim 3 wherein the agonist of nuclearreceptors that activate xenobiotic metabolism is selected from the groupconsisting of constitutive androstane receptor (CAR) agonists, pregnaneX receptor (PXR) agonists, or a peroxisome proliferator-activatedreceptor α (PPARα) agonist.
 5. The dietary supplement or food orbeverage product of claim 3 wherein the agonist of nuclear receptorsthat activate xenobiotic metabolism is clofibrate.
 6. The dietarysupplement or food or beverage product of any of claims 1-5 wherein (b)is diethylenetriaminepentaacetic acid (DTPA).
 7. A dietary supplement orfood or beverage product comprising: (a) Inulin; and (b) Citric acid. 8.The dietary supplement or food or beverage product of claim 7 furthercomprising magnesium or a magnesium salt.
 9. The dietary supplement orfood or beverage product of claim 7 or 8 comprising, per serving: (a)5-10 grams of inulin; and (b) 1-2 grams of citric acid.
 10. The dietarysupplement or food or beverage product of claim 9 further comprising200-300 milligrams of magnesium or a magnesium salt per serving.
 11. Thedietary supplement or food or beverage product of claim 10 comprising250 milligrams of magnesium or a magnesium salt per serving.
 12. Adietary supplement or food or beverage product comprising: (a) Inulin;and (b) Lemon or lime extract, DTPA, EDTA, St. John's wort extract,Hyperforin, Ginkgo bilogoba extract, Ginkgolide A or B, vitamin C,Ascorbic acid 6-palmitate, Pantothenic acid (vitamin B-5), Niacinamide,Allicin (garlic), Lactobionate, Melatonin, Metformin, L-Dopa, extractMucuna beans (Mucuna Dopa), L-Histidine, Quercetin, Curcumin, L-Glutamicacid, succinic acid, N-Acetil Cysteine, Green tea extract,Epigallocatechin-3-gallaye, Glutathione, Aspirin, Salicylate, Glycine,Resveratrol, Genistein, Garnosine, Rapamycin, Lipoic acid, or Taurine.13. The dietary supplement or food or beverage product of claim 12further comprising magnesium or a magnesium salt.
 14. A dietarysupplement or food or beverage product comprising: (a) Inulin; (b) St.John's wort extract, Hyperforin, Ginkgo bilogoba extract, or GinkgolideA or B, Rapamycin; and (c) Citric acid.
 15. The dietary supplement orfood or beverage product of claim 14 further comprising magnesium or amagnesium salt.
 16. The dietary supplement or food or beverage productof any of claims 1-15, wherein the dietary supplement or food orbeverage product is: (a) yogurt; (b) porridge; (c) bread; (d) baby food;(e) a sports drink; (f) an energy bar; (g) chocolate.
 17. The dietarysupplement of any of claims 1-15 in the form of a tablet or capsule fororal ingestion.
 18. A method of attenuating aging, of healthmaintenance, and/or treating or delaying the onset of, an age-relatedcondition or disorder, the method comprising administering to thesubject an effective amount of: (a) one or more compounds that sustainthe pharmacological activation of xenobiotic metabolism or inducefermentation by gut bacteria to produce substances that activatexenobiotic metabolism enzymes and/or stimulate xenobiotic excretion; and(b) one or more chelators.
 19. The method of claim 18, wherein theadministration prolongs the lifespan of the subject relative to thelifespan of the subject in the absence of the administration.
 20. Themethod of claim 18, wherein the administration treats or delays theonset of the age-related disease in the subject relative to the subjectin the absence of the administration.
 21. The method of any one ofclaims 18-20 wherein (a) is inulin.
 22. The method of any one of claims18-20 wherein (a) is an agonist of nuclear receptors that activatexenobiotic metabolism.
 23. The method of claim 22, wherein the agonistof nuclear receptors that activate xenobiotic metabolism is selectedfrom the group consisting of constitutive androstane receptor (CAR)agonists, pregnane X receptor (PXR) agonists, or a peroxisomeproliferator-activated receptor α (PPARα) agonist.
 24. The method ofclaim 22 wherein the agonist of nuclear receptors that activatexenobiotic metabolism is clofibrate.
 25. The method of any of claims18-24 wherein (b) is: Lemon or lime extract, DTPA, EDTA, St. John's wortextract, Hyperforin, Ginkgo bilogoba extract, Ginkgolide A or B, vitaminC, Ascorbic acid 6-palmitate, Pantothenic acid (vitamin B-5),Niacinamide, Allicin (garlic), Lactobionate, Melatonin, Metformin,L-Dopa, extract Mucuna beans (Mucuna Dopa), L-Histidine, Quercetin,Curcumin, L-Glutamic acid, succinic acid, N-Acetil Cysteine, Green teaextract, Epigallocatechin-3-gallaye, Glutathione, Aspirin, Salicylate,Glycine, Resveratrol, Genistein, Garnosine, Rapamycin, Lipoic acid, orTaurine.
 26. The method of any of claims 18-25 wherein (b) isdiethylenetriaminepentaacetic acid (DTPA).
 27. The method of any ofclaims 18-26 wherein the administration prolongs the lifespan of thesubject more than the individual effect of the administration of either(a) or (b).
 28. The method of any of claims 18-27 wherein theadministration prolongs the lifespan of the subject more than the sum ofthe individual effect of the administration of (a) and (b).
 29. Themethod of any one of claims 18-28 further comprising administering tothe subject an effective amount of one or more compound selected fromthe group consisting of: (a) a COX inhibitor; (b) an antiparasiticagent; (c) an acetylcholinesterase inhibitor; (d) an adenosine receptorantagonist; (e) a selective estrogen receptor modulator.
 30. The methodof any one of claims 18-29 further comprising administering to thesubject an effective amount of a magnesium salt.
 31. The method of claim30 wherein the magnesium salt is Magnesium hydroxide, Magnesium acetate,or magnesium chloride.
 32. The method of any one of claims 18-31 furthercomprising administering to the subject an effective amount of citricacid.